Discovery of amiodarone mitochondrial toxicity in liver and beyond

Originally developed as an antianginal agent, amiodarone is now commonly prescribed as a broad-spectrum antiarrhythmic. However, long-term treatment with this pharmaceutical is limited by many drug-drug interactions and various adverse effects affecting different organs and tissues such as the heart, liver, lung, and thyroid. Amiodarone-induced hepatotoxicity includes hepatic cytolysis, cholestasis, and steatosis, a liver lesion which can occur secondary to an impairment of mitochondrial fatty acid oxidation. In this chapter, the discovery of the fact that amiodarone could inhibit this major metabolic pathway in the late 1980s is described. In addition, the fact that this antiarrhythmic drug had a dual effect on oxidative phosphorylation depending on the concentrations applied to isolated mouse liver mitochondria is uncovered. Moreover, the way these mitochondrial effects might favor in some patients the progression of steatosis to steatohepatitis is discussed. Finally, other works showing that amiodarone can alter mitochondrial functions in other tissues such as the lung and thyroid are briefly mentioned.